Immunity vs. Cancer:  fewer side effects with natural killer cells?
Cancer Immunity

Immunity vs. Cancer: fewer side effects with natural killer cells?

Dr. Talia Henkle
Dr. Talia Henkle

In 10 seconds? Natural Killer cells are a type of immune cell that researchers are engineering to tackle blood cancers–which may cause fewer side effects than T cells.

What’s the story? Our Immunity vs. Cancer series has dug into the ways our immune system helps battle cancer. Many new immunotherapies (i.e. drugs that boost our immune system to fight cancer) look to bolster immune cells called T cells, but there’s another important anti-cancer immune cell that is attracting lots of scientific inquiry. Lessons learned from another member of our immune army, Natural Killer cells (AKA NK cells), are encouraging and suggestive that ‘living drug’ cancer therapies (Think CAR-T cells) might not need to be entirely personalized, which has big implications for cost and scalability. NK cells have key differences from T cells that minimize their likelihood of causing dangerous side effects.

Err, care to give me a quick T cell recap? Sure thing! In our digests about T cells, we highlighted their stunning target-specificity as one of their most exciting features as a cancer-fighting tool. T cells can notice mutated cancer-causing or cancer-associated proteins on the surface of cells—when displayed by our cells' internal operations reporting hardware, called MHC. And while extreme specificity is exciting in that it means T cells can kill cancer cells while keeping healthy cells safe, specificity comes with downsides.

Like what? For one, cancer cells can become resistant to targeted approaches if not every cell displays the same T cell targets–which is frequently the case. Secondly, T cells will attack any foreign-looking MHC. That means living CAR-T cell therapies (where living cells are given to patients via IV as treatments) need to be made from a person’s own T cells, instead of from donors. That’s not ideal because personalized processes entail extra doctor appointments, extra needle sticks, and extra medical bills. But it's necessary because T cells from donors will attack the recipient's body broadly and can induce a life-threatening condition called Graft-Versus-Host Disease (GVHD).

OMG… so NK cells can bypass this problem? It looks like it! NK cells, similarly to T cells, can directly kill cancer cells. But instead of looking for specific targets, NK cells look for more general features that indicate a cell needs to be taken out. For example, NK cells are activated by certain stress signals on cells and deactivated by MHC. This is notable because virus-infected and tumor cells frequently ‘hide’ from T cells by lowering the amount of MHC on their surface. That’s where NK cells come in. If NK cells notice ‘stressed out’ cancer cells without MHC, that cell is a goner. With this method of activation, NK cells won’t attack foreign MHC.

And that matters because? NK cells don’t cause Graft-Versus-Host Disease (GVHD)! That’s huge because that means, if the right approach is taken, living NK cell-based therapies could be made from donor cells–saving cancer patients precious time, and hopefully money down the line. To compare: CAR-T cells take 2-3 weeks to engineer after being removed from the patient).

But can NK cells help cure cancer? Yes! In fact, just treating leukemia patients with activated NK cells from donors (without genetic modification) saw impressive results–leading to complete cancer regression in a significant proportion of cases. For example, in one study with 42 patients with poor prognosis acute myeloid leukemia (AML–a type of blood cancer), infusion with activated NK cells from matched donors led to complete remission in 53% of patients and disease-free survival at 6 months in 33% of patients. (Meaning the cancer went away and stayed away for at least 6 months). Lots of similar studies have been conducted with comparable results.

What about solid tumors? Good question. Similar treatment of children with neuroblastoma, a rare type of cancer of the nerve cells, with NK cells also saw promising results. 40% of patients experienced a partial or complete response to the treatment. However, as is the case with CAR-T cells, significant improvements are yet to be seen against solid tumors like breast and ovarian cancer.

Genetic-modification approaches being used to increase anti-tumor properties of NK cells for cancer treatment. Source: Adapted from Simasaki N, et al. Nature Review Drug Discovery. 2020. 19; 200-218

So, what’s next? Researchers are looking for the right combination of treatments to maximize benefits and minimize side effects. CAR-T cell treatment lasts longer and works more potently but also has more serious side effects. Some researchers are engineering CAR-NK cells (see graphic) to increase their potency, and others predict combination treatment with CAR-T cells might balance potency with minimal side effects. Results from ongoing clinical trials should dictate what approaches are the most promising.

Tireless serial killers on a mission to protect us

T cells and NK cells are both serial killers, meaning once activated to attack they can kill many target cells!

They kill by attaching to target cells and injecting them with cytotoxic (AKA cell-killing) proteins.

The main killer is a protein called perforin which will (clue in the name!) perforate the cell membrane, making the cells break open and die.

Remarkably, only one granule of cytotoxic proteins from an NK cell is enough to kill its target!

Dr. Talia Henkle has distilled 3 of research papers saving you 10.5 hours of reading time.

The Science Integrity Check of this 3-min Science Digest was performed by Flávia Oliveira Geraldes.

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